Hypospadias is a birth defect that affects approximately seven in 1,000 male infants in the United States. In affected infants, the urethral openingis located along the underside of the penis, scrotum, or perineum; the condition usually is corrected by surgery. Hypospadias is classified in order of increasingseverity as first, second, or third degree. In 2002, a study in Sweden noted that among male infants born to women who while pregnant had taken loratadine(Claritin®), a nonsedating antihistamine commonly used for seasonal allergies, hypospadias prevalence was twice that of the general population.1 However,insufficient data were available to determine the severity of the hypospadias cases, and the study did not control for confounding variables (eg, familyhistory of hypospadias or maternal age). In 2003, a prospective study using data from four countries indicated that five of 142 pregnancies in women exposedto loratadine resulted in infants with major malformations, a prevalence consistent with that of the general population; none had hypospadias.2 Tofurther assess any potential association between loratadine and hypospadias, CDC analyzed data from the National Birth Defects Prevention Study (NBDPS).This report summarizes the results of that analysis, which determined that no increased risk for second- or third-degree hypospadias existed among womenwho used loratadine in early pregnancy (Table 1). These results might be useful for women and health-care providers to address concerns about loratadine use and hypospadias.

Risk for hypospadias in male infants associated with exposure to loratadine and nonsedating and sedating antihistamines — NationalBirth Defects Prevention Study, United States, October 1997–June 2001

NBDPS is an ongoing, multistate, case-control study of environmental and genetic risk factors for major birth defects that can be used in responseto public health concerns regarding rare drug exposures and birth defects.3,4 In fants are identified through birth defect surveillance systems in eight states; mothers undergo a detailedinterview by telephone in English or Spanish. For this analysis, the case population was defined as male infants with second- or third-degree hypospadias.Infants with first-degree hypospadias are not included in NBDPS because the mildest form of hypospadias is much less completely ascertained by routinesurveillance. Infants were excluded if they had 1) known or suspected chromosome abnormalities, 2) single gene conditions, or 3) other recognized multiplecongenital anomaly phenotypes. The control population consisted of live-born male infants with no major birth defects, selected at random from the samepopulations as the case group. Excluded from the analysis were 86 infants whose mothers had incomplete interviews and 30 infants (28 in the case populationand two in the control population) who had fathers or brothers with hypospadias. The study populations consisted of 563 male infants with hypospadias and 1,444male infant controls; all were born during October 1, 1997–June 30, 2001.

Exposure was defined as any maternal use of loratadine from 1 monthbefore pregnancy through the first trimester. To control for confounding byindication, exposure to other nonsedating or sedating antihistamines during the same period also was assessed. Potential confounding factors tested bymultivariate logistic regression analysis included maternal age, maternal race/ethnicity (ie, non-Hispanic white, non-Hispanic black, Hispanic, andother), birth month, and state of residence at delivery.

Of 563 male infants with hypospadias, 46 (8.2%) had multiple major birth defects that were not recognized phenotypes, and 517 (91.8%) had hypospadiaswith no other major birth defects. Among the 1,957 mothers of infants in thecase and control populations, 33 (1.7%) reported using loratadine during theexposure period. Univariate analyses showed no association between this use of loratadine and hypospadias (Table 1).Use of nonsedating antihistamines (including loratadine) and sedating antihistaminesalso were not associated with hypospadias. Multivariate adjusted odds ratioestimates did not vary significantly from the univariate estimates. In addition, no association between loratadine use and hypospadias was determined whencases with multiple major defects were excluded or when different exposure periods were examined.

The findings in this report indicated that hypospadias was not associated with use of loratadine during the period from 1 month before pregnancy throughthe first 3 months of pregnancy. During 1998-1999, loratadine was the drug most advertised directly to consumers5 andwas used by 3% of women of childbearing age.6 InNovember 2002, loratadine was approved by the Food and Drug Administrationfor over-the-counter use.7 Antihistamines are used widely by the general population, including women of childbearingage, 20%-30% of whom have allergic conditions, primarily rhinitis and sinusitis.8 Because an estimated 50% of all pregnancies in the United States are unintended,9 womenfrequently are exposed inadvertently to medications before learning they are pregnant.

This report is subject to at least two limitations. First, NBDPS does not track all birth defects. Because first-degree hypospadias is excluded,the potential association between this mildest form of hypospadias and loratadine could not be assessed. Second, women are interviewed about their pregnancyexposures after delivery, and recall of drug use might be different among mothers of infants with major birth defects compared with mothers of infantswithout major birth defects.

The results of this analysis might be useful for women and health-careproviders to address concerns about loratadine use and hypospadias. Theseresults do not provide definitive information on the overall safety of loratadine. Women should continue to consult their health-care providers before usingany medications during pregnancy. Future studies of medications and birth defects, possibly using NBDPS, are needed to address some of the current knowledgegaps on the effects of medication use during pregnancy.